Obesity and type 2 diabetes mellitus (T2DM) are both complex diseases with multifactorial etiologies. Together they affect over 640 million people worldwide and have a significant impact on the global healthcare system incurring costs of over 800 billion dollars. The overall goal of my doctoral research has been to elucidate metabolic predictors and underlying mechanisms in obesity and T2DM. Specifically, I have examined mechanisms contributing to disordered oxidative metabolism in skeletal muscle. My research included participants who were recruited from the Ottawa Hospital Weight Management Clinic in which they completed a clinically supervised meal-replacement and lifestyle intervention program. More so, my doctoral studies evaluated characteristics of muscle mitochondrial function in obesity and T2DM and revealed impaired mitochondrial respiration and electron transport chain supercomplex assembly in muscle from patients with T2DM. The first aim was to study the impact of T2DM on weight loss ability in a large population of obese patients participating in a standardized meal replacement and lifestyle modification program. As there is considerable variability in weight loss propensity, it was found that T2DM significantly deters weight loss although the effect is not large. Since skeletal muscle energetics are central in the development and progression of obesity and T2DM, the second and third aims were to study mitochondrial function in this tissue with the idea of uncovering molecular etiologies. The second aim found deficiencies in mitochondrial respiration in individuals with obesity and T2DM compared to individuals with obesity alone. Reductions in mitochondrial respiration were correlated with increasing levels of HbA1C and attributed to paucity in supercomplex formation in the mitochondrial inner membrane (MIM) of the electron transport chain (ETC). The third aim was to delineate differential fuel oxidation mechanisms and circulating protein biomarkers in obese diet-sensitive (ODS) and obese diet-resistant (ODR) participants following a high fat meal (HFM) challenge. Whole-body analyses were conducted in addition to measures in blood, adipose tissue, skeletal muscle and primary cells. Remarkable increases in oxidative capacity were measured post-HFM. In addition, impaired mitochondrial function was found in the ODR group despite lack of differences in mitochondrial content or the assembly of supercomplexes. Differences were also found in circulating acylcarnitines as well as expression of several proteins including Heat shock 70 kDa protein 1A/1B, Tyrosine-protein kinase Fgr, and Peptidyl-prolyl cis-trans isomerase D. Ultimately, a better understanding of mechanisms involved could lead to significant improvements in personalized medical approaches in obesity and T2DM.

abstract: This dissertation was guided by the Ecological Model of Physical Activity and Ecological Model of Obesity and sought to determine the relationship between active transportation (AT), physical activity, and cardiometabolic health among adults and ethnic minority women. Chapter 2 presents an investigation into the relationship between walking for AT and cardiometabolic health among adults through systematic review. Chapter 3 presents an exploration of the cross-sectional relationships of AT and moderate-to-vigorous physical activity (MVPA) with cardiometabolic health among African American (AA) and Hispanic/Latina (HL) women from Texas. Chapter 4 presents an investigation into the cross-sectional relationship of AT on cardiometabolic health and physical activity among primarily HL women. In Chapter 2, walking for AT was found to be related to smaller waist circumference, lower blood pressure, and lower prevalence of abdominal obesity and hypertension, and that differences may exist based on sex. Walking for AT was not clearly defined, and criteria used to determine the presence of cardiometabolic outcomes were inconsistent. No significant relationships between AT and cardiometabolic health were found in Chapter 3 or 4; however, AT users had slightly better cardiometabolic health. AT users had significantly higher levels of self-reported total physical activity compared to those who did not use AT in Chapter 3. Furthermore, a significant relationship was found between MVPA and diastolic blood pressure. Associations differed by ethnicity, with MVPA being inversely related to body fat in both AA and HL women, but to body mass index only in AA women. AT users were found to be seven times more likely to meet 2018 national MVPA recommendations than non-AT users in Chapter 4. Across all studies, measures of AT were subjective and of low quality, potentially limiting the ability to detect significant findings. High quality randomized controlled studies should be conducted using clearly defined, objective measures of AT, and analyzed based on sex and race/ethnicity. Clinicians should recommend AT use to promote meeting MVPA recommendations where appropriate, potentially resulting in improved cardiometabolic health. Policymakers should advocate for changes to the built environment to encourage AT use and MVPA to improve public health. / Dissertation/Thesis / Doctoral Dissertation Nursing and Healthcare Innovation 2019

Magister Artium (Sport, Recreation and Exercise Science) - MA(SRES) / Obesity is recognised as a risk factor for non-communicable diseases which has reached epidemic proportions globally. South Africa is one of the developing countries with significant statistical representation reported for these conditions. Obesity is associated with other conditions such as type 2 diabetes, hypertension and dyslipidaemia which are all part of what is called metabolic syndrome. As a strategy to reduce the levels of obesity, physical activity has been introduced to compliment clients who are on medication for diabetes.

Objective: To assess whether the prevalence of low physical activity levels and time spent watching TV differ depending on glycemia status. Methods: A secondary analysis using data from a population-based study was conducted. Two were the outcomes: physical activity levels, derived from the International Physical Activity Questionnaire, and sitting time watching TV. The exposure was glycemia status, defined based on results of the oral glucose tolerance tests (OGTT): euglycemia, dysglycemia, and T2DM. The T2DM group was further split into: aware and unaware of T2DM diagnosis. Prevalence ratios (PR) and 95% CI were reported using Poisson regression models. Results: Data of 1607 individuals, mean age 48.2 (SD: 10.6) years, 809 (50.3%) females, were analyzed. Dysglycemia and T2DM was present in 16.9% (95% CI: 15.1%–18.8%) and 11.0% (95% CI: 9.5%–12.6%) of participants, respectively. A total of 605 (37.6%; 95% CI: 35.2%–39.9%) participants had low levels of physical activity and 1019 (63.3%; 95% CI: 60.9%–65.7%) subjects spent ≥2 h per day sitting watching TV. In multivariable model, there was no significant association between glycemia status and physical activity levels (PR = 1.14; 95% CI: 0.95–1.36). Similar result was found between glycemia status and sitting time watching TV. However, those aware of T2DM diagnosis were more likely to have low levels of physical activity (PR = 1.31; 95% CI: 1.06–1.61) compared to the euglycemia group. Conclusions: We found a no relationship between glycemia status and physical activity level or sitting time watching TV, pointing out similar levels of physical (in)activity among those with euglycemia, dysglycemia and T2DM. Individuals aware of having T2DM were 30% more likely to have low physical activity levels compared to the euglycemic group. There is a need to increase physical activity levels among T2DM individuals. / Revisión por pares

Objectives To evaluate the effectiveness of pharmacist-physician collaboration in the treatment of type 2 diabetes mellitus (DM) with severe insulin resistance, using 500 U/mL concentrated regular insulin (U-500) in a primary care clinic that is not staffed by an endocrinologist. Methods A retrospective chart review was conducted searching for patients who were prescribed U-500 insulin from January 1, 2008 through December 31, 2014. Subjects were included in the analysis if the pharmacist initiated U-500 insulin therapy, received treatment for at least 6 months, and who attended at least one follow-up visit with the pharmacist. Anyone who received U-500 insulin before the initial pharmacist consultation, managed by an endocrinologist, or who was missing follow-up hemoglobin A1c (HbA1c) laboratory values during the follow-up period was excluded. The primary endpoint was the change in HbA1c from U-500 initiation to 6 months later. Secondary endpoints included changes in weight, confirmed hypoglycemia events, changes in other anti-DM medications and the number of pharmacist and primary care physician visits during the follow-up period. Results Eighty-one patients were identified and screened, and 44 patients were included in the analysis. Baseline HbA1c (mean ± standard deviation) was 9.7% ± 1.6% and decreased to 8.6% ± 1.6% after 6 months of follow-up, representing a reduction of 1.1% (95% confidence interval -1.6 to -0.6, P < 0.001). Body weight increased (mean ± standard deviation) by 6.7 ± 15.1 lb from baseline (P = 0.005). The frequency of confirmed hypoglycemia events was low (0.8 events per patient). Treatment with metformin was preserved, whereas most other DM medications were discontinued. A similar number of pharmacist and physician follow-up visits were completed by the end of the study period (2.0 and 2.7 visits, respectively; P = 0.805). Conclusions Initiation of U-500 insulin by clinical pharmacists collaborating with primary care physicians results in improved DM control in patients with severe insulin resistance. Our findings suggest this interprofessional partnership provides an alternative referral approach for primary care physicians when endocrinology services are absent or limited.

Background: One-third of the U.S. population has prediabetes, but 90% remain undiagnosed because healthcare providers are not screening for this condition. Objective: The purpose of this quality improvement project was to monitor prediabetes screening and identification, and implement evidence-based recommendations including registered dietician referral. Methods: This project involved using an evidence-based screening tool to measure individual risk of prediabetes. Aggregate data was collected to evaluate screening implementation, evidence-based recommendations offered by providers, and assess patient risk factors. Results: The percentage of patients at risk for prediabetes was 41.3% (n = 111). The most frequent risks were identified as overweight, history of hypertension, family history of type 2 diabetes mellitus (T2DM), and older age. Providers offered education on weight loss 68.5% (n = 76) and exercise 76.6% (n = 85) but referred 33.3% (n = 37) patients for nutrition education. The screening rates were 52.3% (n = 176) and 72.5% (n = 244) in clinics A and B respectively. Conclusions: A gap remains in using evidence-based recommendations to decrease risk of prediabetes. Prediabetes screening identified a greater percentage of persons in this population. Implications for Nursing: There is a need for consistent practice of evidence-based recommendations. This project set the benchmark for future efforts to educate, encourage, and measure providers successes.

BACKGROUND In 2010, glycated haemoglobin A1c (HbA1c) was officially recommended as a screening tool to diagnose type 2 diabetes mellitus (T2DM) and pre-diabetes, with cut-off points 6.5% and 5.7% to 6.4% respectively. The implications of using the HbA1c criterion, compared to the general diagnostic criteria: fasting glucose test (FPG) and oral glucose tolerance test (OGTT), is however still being debated. OBJECTIVES The objectives of this study were to evaluate and compare the pooled prevalence of type 2 diabetes mellitus (T2DM) and pre-diabetes, as measured by the Haemoglobin A1c (HbA1c) test, or the fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT). Secondly, to determine and compare the diagnostic test characteristics (sensitivity, specificity) of these tests. METHODS Published papers, with a cross sectional study design, were selected for a systematic review and meta-analysis. The search strategy was an electronic review of journal articles listed on MEDLINE, PubMed and Google scholar between 1996 and 2012. Reference lists were checked, journals were hand searched and experts were contacted when necessary. Initially all studies related to the validation of HbA1c as a tool to detect pre-diabetes or T2DM in humans, published in English, were examined. Studies were excluded if they did not meet the above mentioned criteria, and/or were conducted with pregnant women. Further analysis was done if FPG or OGTT was compared to HbA1c. The diagnosis of diabetes had to have been based on ADA or WHO criteria. These criteria are: HbA1c 5.7%-6.4% for pre-diabetes and >=6.5% for T2DM; FPG 5.6mmol-7mmol/l for pre-diabetes and >=7mmol/l for T2DM; OGTT 7.8mmol-11.1mmol/l for pre-diabetes and >=11.1mmol/l for T2DM). The OGTT and FPG tests were used as the reference tests and the prevalence reflected as a positive or negative proportion. The sensitivity and specificity of HbA1c >=6.5% among cases defined by OGTT or FPG should have been reported, or it was possible to calculate these from the data provided. Study results relating to diagnostic accuracy were extracted and synthesized using multivariate random effects meta-analysis methods. This study focused on patients who were suspected of having T2DM, from two sub-groups (a community-based group and a high-risk group) to compare the detection rate of HbA1c with FPG and OGTT. / Dissertation (MSc)--University of Pretoria, 2014. / lk2014 / School of Health Systems and Public Health (SHSPH) / MSc / Unrestricted

Both plasma glucose concentration and glucose uptake are deranged in insulin resistance. A high free fatty acid plasma level is a potential cause of insulin resistance, and therefore of type 2 diabetes mellitus animals and humans. The mechanism behind this is still unclear. The objectives of the present study were: (i) to research the effect of arachidonic acid (AA) as fatty acid representative, on glucose uptake into human isolated adipocytes, (ii) to investigate the uptake of AA into adipocyte membranes and nuclei, as a step to identify the mechanism whereby AA affects glucose uptake, and (iii) to verify the influence of insulin on AA uptake in adipocytes. The first objective was achieved by exposing adipocytes to AA and measuring the effect on deoxyglucose uptakt. To achieve the second objective, adipocytes were exposed to 14C-AA; radioactive uptake in membranes and nuclei was determined. The AA uptake into membranes was also determinate by membranes fatty acid profile using gas chromatography; the results of the two methods were compared. Finally, the third objective was achieved by exposing adipocytes to different concentrations of insulin and testing the effect by measuring arachidonic acid uptake by the entire cell. The results of this study shown that, acute (30 min) exposure of AA significantly stimulates glucose uptake by adipocytes (4.56 ± 0.6 nmole glucose /mg protein /min) compared to the control (3.12 ± 0.25 nmole glucose /mg protein /min). Secondly, 14C-AA was significantly taken up by the membranes between 20 and 30 minutes of exposure. The uptake into membranes was increased by 49.57 ± 29% and 123 ± 73% compared to the control 100% (1.77 ± 0.06 nmole AA /mg protein) respectively for 20 and 30 min exposure). AA significantly rose in the nuclei after 30 minutes (147 ± 19% increase) compared to the control 100% (2.25 ± 0.10 nmole AA /mg protein). The determination of AA uptake by gas chromatography analysis of the membrane fatty acid profile showed that the content of AA increased after 30 min exposure (0.57% AA of total membrane fatty acids) compared to the 10 min exposure (0.29% AA of total membrane fatty acid). Insulin was shown to stimulate 10 and 30 min AA uptake by adipocytes from a non-obese subject. The increases of AA uptake measured for 30 minutes were 20 ±8%, 21 ± 25% and 31 ± 4% compared to the control (0.58nmole AA / mg protein / min) respectively for the actions of 10nM, 20nM and 40 nM insulin. A similar tendency was observed when the AA uptake was measured for 10 min (81 ± 31% and 208 ± 36% respectively for the action of 10nM and 40nM insulin compared to the control 100% (0.06nmole AA/mg protein/min). In contrast to this finding, insulin depressed AA uptake by adipocytes from an obese subject (depression of 15 ± 5%, 14 ± 8% and 21 ± 5% respectively for 10nM, 20nM and 40nM insulin, compared to the control 100% (0.74 nmole AA/mg protein/min). In both situations the effect of insulin seemed dose dependent. The study demonstrated that AA acid positively modulates glucose uptake into adipocytes exposed for short periods (< 30 min). This was attributed to the probable this FA in the cell membrane, rather than its eventual effect on the DNA. The best method to measure membranes AA over short period of exposure when small amounts of adipocytes (2- 6 ml) are used was by radioactive means. It also suggested that insulin effect’s on AA acid uptake into adipocytes was dose dependent. This varies with the body mass index (BMI) of the patient, probably as a result of their cell’s insulin resistant state. / Dissertation (MSc (Veterinary Science))--University of Pretoria, 2007. / Anatomy and Physiology / MSc / unrestricted

Type 2 diabetes mellitus (T2DM) is classified as a metabolic disorder characterized by hyperglycemia that results from defects in insulin action and/or secretion, and currently affects 8.3% of the US population according to the CDC’s 2011 National Diabetes Fact Sheet. Several contributing factors have been identified to development of this disease. Published evidence indicates type 2 diabetes mellitus (T2DM) patients display lower overall paraoxonase activity and that this may be partially due to genetic variations in the paraoxonase-1 (PON-1) gene. Some bioaccumulative organochlorine (OC) pesticides have been shown to contribute to increased T2DM prevalence. In addition, these OC compound levels have been associated with alterations in adipocyte cytokine levels as well as increased inflammatory markers. Three hundred blood samples with clinical and demographic information were obtained from two US Air Force hospitals. A total of 151 non-diabetics and 149 T2DM subjects were evaluated for PON-1 activity, PON-1 Q192R and L55M genetic polymorphisms, OC compound concentrations, inflammatory marker levels and adipokine concentrations. PON-1 activity, using diazoxon as the substrate, was decreased in the T2DM subjects. Some of the PON-1 genetic polymorphisms tested were also associated with decreased PON-1 activity. OC compound levels were increased in the T2DM subjects. The non-diabetic subjects possessing elevated DDE and trans-nonachlor were associated with increased inflammation, a common hallmark of early T2DM development. Additionally, elevated OC levels were seen in association with altered adipokine concentrations. Overall, a decrease in the antioxidant properties of PON-1 as well as factors contributing to chronic low level inflammation such as elevated OC plasma concentration appear to be significant contributors to T2DM prevalence in the population studied.

Background: Over the last decade, diabetes health coaching, also referred to as diabetes coaching, has emerged as a patient-centered intervention to assist individuals with type 2 diabetes mellitus (T2DM) in acquiring independence with self-management. The structure and delivery of such interventions have varied greatly while showing improvements in glycemic control. However, literature continues to show a gap around the patient experience of receiving diabetes coaching support. Objective: To explore the perceived experience of receiving telephone-based diabetes health coaching among community-based adults with T2DM within the Canadian context. Methods: A qualitative exploration with an interpretive descriptive design was carried out. Participants from the intervention group of a larger randomized controlled trial who had received a telephone-based diabetes coaching intervention over one year were invited to participate in a telephone interview with open-ended questioning. Findings: A total of 12 participants were interviewed and four major themes were identified. (1) Adapting to life with T2DM reflects how coaching helped individuals to integrate diabetes into their lives by addressing misconceptions, providing knowledge, encouraging awareness, and easing transition onto insulin. (2) Heightened mindfulness of diabetes-related wellness captured the greater attention participants’ gave to their overall well-being and self-management behaviours. (3) Behaviour change guided by the participant highlights the differences in participants’ motivation, readiness to make changes, external factors that influenced their ability to make self-management behaviour changes. (4) Lastly, valuing a supportive relationship illustrates that participants felt the unique coach-client relationship was reliable, holistic, non-judgmental, and encouraging. Conclusion: Overall, participants found diabetes coaching to be positive and highlighted the various ways it was able to support their ability to more effectively self-manage their diabetes. / Thesis / Master of Science in Nursing (MSN)